neuropeptide-y and Alzheimer-Disease

There is currently no effective treatment either for neurological illnesses (ischemia and neurodegenerative diseases) or psychiatric disorders (depression), in which the Glu/GABA balance is disturbed and accompanied by significant excitotoxicity. Therefore, the search for new and effective therapeutic strategies is imperative for these disorders. Studies conducted over the last several years indicate that the neuropeptide Y (NPY)-ergic system may be a potential therapeutic target for neuroprotective or antidepressant compounds. This review focuses on the neuroprotective roles of Y2 and Y5 receptors (YRs) in neurological disorders such as ischemia, Alzheimer's disease, Parkinson's disease, Huntington's disease, and in psychiatric disorders such as depression. It summarizes current knowledge on the possible mechanisms underlying the neuroprotective or antidepressant-like actions of Y2R and Y5R ligands. The review also discusses ligands acting at Y2R and Y5R and their limitations as in vivo pharmacological tools. The results from the preclinical studies discussed here may be useful in developing effective therapeutic strategies to treat neurological diseases on the one hand and psychiatric disorders on the other, and may pave the way for the development of novel Y2R and Y5R ligands as candidate drugs for the treatment of these diseases.

Topics: Alzheimer Disease; Animals; Depression; Drug Discovery; Humans; Huntington Disease; Ischemia; Mice; Neuropeptide Y; Neuroprotection; Receptors, Neuropeptide Y; Synapses

Alzheimer's disease (AD) is a disorder characterized by the accumulation of abnormally folded protein fragments in neurons, i.e., β-amyloid (Aβ) and tau protein, leading to cell death. Several neuropeptides present in the central nervous system (CNS) are believed to be involved in the pathophysiology of AD. Among them, neuropeptide Y (NPY), a small peptide widely distributed throughout the brain, has generated interest because of its role in neuroprotection against excitotoxicity in animal models of AD. In addition, it has been shown that NPY modulates neurogenesis. Interestingly, these latter effects are similar to those elicited by neurotrophins, which are critical molecules for the function and survival of neurons that degenerate during the course of AD. In this review we summarize the evidence for the involvement of NPY and neurotrophins in AD pathogenesis, and the similarity between them in CNS neurons. Finally, we recapitulate our recent in-vitro evidence for the involvement of neurotrophin nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) in the neuroprotective effect elicited by NPY in AD neuron-like models (neuroblastoma cells or primary cultures exposed to toxic concentrations of Aβ's pathogenic fragment 25-35), and propose a putative mechanism based on NPY-induced inhibition of voltage-dependent Ca(2+) influx in pre- and post-synaptic neurons.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Calcium Channels; Cell Line, Tumor; Cell Survival; Humans; Nerve Growth Factors; Neurons; Neuropeptide Y; Neuroprotective Agents

Topics: Adrenal Gland Neoplasms; Alzheimer Disease; Anorexia Nervosa; Autonomic Nervous System Diseases; Biomarkers; Humans; Hypertension; Immunoradiometric Assay; Neuroblastoma; Neuropeptide Y; Pheochromocytoma; Radioimmunoassay; Reference Values

Neuropeptide Y (NPY) and peptide YY (PYY) are members of the pancreatic polypeptide family which have a high degree of primary and tertiary structural homology. They function as neurotransmitters and humoral agents in central nervous system and gastrointestinal function. During the last two decades, NPY body fluid concentrations and NPY/PYY brain receptor numbers have been demonstrated to be altered during the course of Alzheimer's disease. Recent research has shown that both NPY and PYY may be involved in aluminum metabolism in animal models. A brief discussion of the structure, biological activity and possible involvement of these peptides in aluminum metabolism and Alzheimer's disease is contained herein.

Topics: Aluminum; Alzheimer Disease; Animals; Humans; Neuropeptide Y; Peptide YY; Protein Conformation

Neuropeptide Y is a 36-amino acid peptide that is widely distributed in the brain. Recently, three neuropeptide Y receptor subtypes were discovered with the aid of peptidergic agonist analogs of neuropeptide Y. Many researchers reported that neuropeptide Y might be involved in locomotor activity, eating behavior, stress responses, memory processing, circadian rhythms, blood pressure and neuroendocrine functions. It was also reported to interact with sigma receptor and corticotropin-releasing factor. Clinical evidence suggests that neuropeptide Y might be related to depression, schizophrenia, anorexia nervosa and Alzheimer's disease. In this review, central distribution and receptor subtypes of neuropeptide Y, its physiological action and its levels in cerebrospinal fluid and plasma in psychiatric and neurological illnesses are described.

Topics: Alzheimer Disease; Animals; Brain; Depression; Humans; Memory; Motor Activity; Neuropeptide Y; Receptors, Neuropeptide Y; Receptors, sigma; Stress, Physiological

Topics: Alzheimer Disease; Amygdala; Animals; Arecoline; Avoidance Learning; Feeding Behavior; Hippocampus; Humans; Memory; Mice; Neuropeptide Y; Neuropeptides; Tachykinins; Thalamus

A large number of neuropeptides have been found in cortical neurons. They are therefore of interest in attempting to demonstrate selective vulnerability of different populations of neurons in Alzheimer's disease (AD). The most consistent neuropeptide deficit in AD is reductions in cortical concentrations of somatostatin. Lesser reductions in corticotropin-releasing factor, neuropeptide Y and substance P have been reported. Concentrations of both vasoactive intestinal polypeptide and cholecystokinin are relatively preserve. The morphologic correlate of reduced somatostatin concentrations in AD appears to be markedly distorted and reduced terminal fiber plexuses, rather than reduced numbers of neuronal perikarya. A large number of neuropeptides have been localized in senile plaques.

Topics: Alzheimer Disease; Brain Chemistry; Humans; Neuropeptide Y; Neuropeptides; Somatostatin; Substance P

Topics: Alzheimer Disease; Basal Ganglia; Brain; Brain Chemistry; Cerebral Cortex; Choline O-Acetyltransferase; Enkephalin, Methionine; FMRFamide; gamma-Aminobutyric Acid; Glutamate Decarboxylase; Humans; Huntington Disease; Nerve Tissue Proteins; Neurofibrils; Neuropeptide Y; Neurotensin; Oligopeptides; Peptides; Substance P; Tyrosine 3-Monooxygenase; Vasoactive Intestinal Peptide

The anatomic distribution of classical neurotransmitters, i.e. NA, DA, 5HT, ACH and GABA in the post-mortem autopsied brain of Alzheimer's disease (AD) has been reviewed. In addition, the results and reviews reported in this paper give evidence for the change of a large number of neuropeptides in AD on the basis of immunohistochemical criteria. Among numerous peptidergic systems, abnormalities in SP, SS, NT and VIP have been observed. Therefore, no changes in the concentrations of CCK and TRH were reported. In this study, using immunohistochemical methods for SS changes in post-mortem brain material of three cases of AD and two controls, the following changes were observed: An important reduction of the SS-positive cell bodies and fibres in the cortex, the hippocampus, parahippocampic cortex, and neocortex, particularly in the parietal and frontal areas, as well as a reduction of SS cell bodies and fibres in the sub-cortical white matter. An amorphous SS-positive material in or close to the corona of a number of senile plaques. An important decrease of SS fibres and cell bodies in the lateral septi nuclei. An increase of the number and immunoreactive intensity of SS-positive fibres in the substantia innominata. In animal studies, an interaction between SS- and ACH turnover in the substantia innominata is reported. The GABA decrease as well as the SS deficit in the cortex area and sub-cortical white matter may lead to the interaction between SS and other neurotransmitters in AD.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Brain Chemistry; Cholecystokinin; Choline O-Acetyltransferase; Humans; Middle Aged; Neuropeptide Y; Neuropeptides; Somatostatin; Substance P; Vasoactive Intestinal Peptide

Topics: Adenylyl Cyclase Inhibitors; Alzheimer Disease; Amygdala; Animals; Basal Ganglia; Behavior, Animal; Brain Stem; Cell Membrane Permeability; Central Nervous System; Cerebral Cortex; Chemical Phenomena; Chemistry; Hippocampus; Humans; Huntington Disease; Hypothalamus; Insulin; Insulin Secretion; Molecular Weight; NADPH Dehydrogenase; Nerve Tissue Proteins; Nervous System Diseases; Neuropeptide Y; Receptors, Cell Surface; Receptors, Somatostatin; Septal Nuclei; Somatostatin; Spinal Cord; Substantia Innominata

The discovery of neuropeptides in mammalian nervous tissue has proceeded at an astonishing pace in recent years, encouraged by novel detection techniques which allow peptides to be extracted and sequenced before their biological activity has been determined (Mutt 1983; Sudcliffe et al. 1983). Most of these methods, poached from molecular biology, are nowadays reversing former trends which evolved either as a systematic search for factors known to control pituitary hormone release (vasopressin and oxytocin), for instance, or as an endeavour to find endogenous ligands for newly discovered receptors (the endorphins) (see Krieger 1983 for review). Neuropeptide tyrosine (NPY) has emerged as an important member of this new generation of peptides, not least because it is the most abundant and widely distributed in the mammalian brain. However, despite the considerable attention this peptide has attracted, we are far from understanding its functional significance. The following account traces the history of NPY and appraises some of the literature in an attempt to raise some speculation concerning its function; several reviews on this peptide already exist (Emson and de Quidt 1984; Solomon 1985; Allen and Bloom 1986; Gray and Morley 1986), Particular attention is paid to studies which have recently suggested that NPY might be involved with the pathogenesis of two neurodegenerative disorders, Huntington's chorea and Alzheimer's disease.

Topics: Alzheimer Disease; Animals; Brain; Cats; Humans; Huntington Disease; Neuropeptide Y; Rabbits; Rats

Neuropeptide Y (NPY) is demonstrated to be involved in the pathophysiology of Alzheimer's disease, as well as somatostatin. We measured the plasma NPY content in patients with Alzheimer's disease and healthy control subjects (n = 25) by HPLC coupled with radioimmunoassay. The difference in screening pattern of NPY-like immunoreactivity in 50 fractions eluted by HPLC obtained from the plasma peptide-rich fraction between patients with Alzheimer's disease and healthy controls suggested the abnormal metabolism of plasma NPY in patients with Alzheimer's disease. Plasma NPY in patients with Alzheimer's disease was significantly decreased compared with that in healthy controls, which was compatible with the findings obtained from the brain and cerebrospinal fluid and could be involved in the pathogenesis or pathophysiology of Alzheimer's disease.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Chromatography, High Pressure Liquid; Female; Humans; Male; Middle Aged; Neuropeptide Y; Radioimmunoassay

Neuropeptide Y (NPY) is a 36 amino acid peptide that regulates a multitude of physiological functions in the central nervous system and has been shown to be involved in Alzheimer's disease (AD). A change in copper homeostasis is a remarkable feature of AD, and the dysregulation may contribute to toxicity in neural cells. Moreover, it has been shown that copper could interact with many neuropeptides and result in catalyzing the production of reactive oxygen species, which may lead to peptide oxidation. Besides, copper could also catalyze protein tyrosine nitration under oxidative stress, and there are two tyrosine residues playing an important role in NPY. Therefore, it is also likely that copper has an action on NPY and potentially influences its functions through tyrosine nitration. In this paper, the studies of the interaction of copper with NPY and the copper-catalyzed NPY nitration were performed. The electrochemical techniques, UV-vis spectroscopy, mass spectrometry, and fluorescence titration, have been applied to show that copper can interact with NPY to form a Cu-NPY complex with a conditional dissociation constant of 0.021 μmol/L, and the binding promotes the generation of •OH. Dot blotting results reveal that NPY can be nitrated upon binding with copper under nitrative stress. Furthermore, liquid chromatography-mass spectrometry (LC-MS) identify that the tyrosine residues in NPY are all nitrated during the nitration process, which will cause the inactivation of NPY shown by our previous study. This study supports the hypothesis that copper has a close correlation with NPY and implicates the peptide in AD. These data may provide a new insight into understanding the pathology and pathogenesis of AD.

Topics: Alzheimer Disease; Chromatography, Liquid; Copper; Electrochemical Techniques; Humans; Neuropeptide Y; Nitrates; Nitrosative Stress; Oxidative Stress; Protein Binding; Spectrometry, Fluorescence; Spectrometry, Mass, Electrospray Ionization; Spectrophotometry, Ultraviolet; Tyrosine

Neuropeptide Y (NPY) is one of the most abundant protein transmitters in the central nervous system with roles in a variety of biological functions including: food intake, cardiovascular regulation, cognition, seizure activity, circadian rhythms, and neurogenesis. Reduced NPY and NPY receptor expression is associated with numerous neurodegenerative disorders including Alzheimer disease (AD). To determine whether replacement of NPY could ameliorate some of the neurodegenerative and behavioral pathology associated with AD, we generated a lentiviral vector expressing NPY fused to a brain transport peptide (apoB) for widespread CNS delivery in an APP-transgenic (tg) mouse model of AD. The recombinant NPY-apoB effectively reversed neurodegenerative pathology and behavioral deficits although it had no effect on accumulation of Aβ. The subgranular zone of the hippocampus showed a significant increase in proliferation of neural precursor cells without further differentiation into neurons. The neuroprotective and neurogenic effects of NPY-apoB appeared to involve signaling via ERK and Akt through the NPY R1 and NPY R2 receptors. Thus, widespread CNS-targeted delivery of NPY appears to be effective at reversing the neuronal and glial pathology associated with Aβ accumulation while also increasing NPC proliferation. Overall, increased delivery of NPY to the CNS for AD might be an effective therapy especially if combined with an anti-Aβ therapeutic.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Apolipoproteins B; Cell Proliferation; Central Nervous System; Disease Models, Animal; Gene Transfer Techniques; Genetic Therapy; Humans; Mice; Mice, Transgenic; Neural Stem Cells; Neurogenesis; Neurons; Neuropeptide Y; Rats

Cortical and hippocampal hypersynchrony of neuronal networks seems to be an early event in Alzheimer's disease pathogenesis. Many mouse models of the disease also present neuronal network hypersynchrony, as evidenced by higher susceptibility to pharmacologically-induced seizures, electroencephalographic seizures accompanied by spontaneous interictal spikes and expression of markers of chronic seizures such as neuropeptide Y ectopic expression in mossy fibers. This network hypersynchrony is thought to contribute to memory deficits, but whether it precedes the onset of memory deficits or not in mouse models remains unknown. The earliest memory impairments in the Tg2576 mouse model of Alzheimer's disease have been observed at 3 months of age. We thus assessed network hypersynchrony in Tg2576 and non-transgenic male mice at 1.5, 3 and 6 months of age. As soon as 1.5 months of age, Tg2576 mice presented higher seizure susceptibility to systemic injection of a GABAA receptor antagonist. They also displayed spontaneous interictal spikes on EEG recordings. Some Tg2576 mice presented hippocampal ectopic expression of neuropeptide Y which incidence seems to increase with age among the Tg2576 population. Our data reveal that network hypersynchrony appears very early in Tg2576 mice, before any demonstrated memory impairments.

Topics: Age Factors; Alzheimer Disease; Analysis of Variance; Animals; Biomarkers; Electroencephalography; Electroencephalography Phase Synchronization; GABA-A Receptor Antagonists; Immunohistochemistry; Male; Mice; Mice, Transgenic; Nerve Net; Neuropeptide Y; Seizures

Alzheimer disease (AD) is characterized by widespread neurodegeneration throughout the association cortex and limbic system, deposition of amyloid-β peptide (Aβ) in the neuropil and around the blood vessels, and formation of neurofibrillary tangles. The endopeptidase neprilysin has been successfully used to reduce the accumulation of Aβ following intracranial viral vector delivery or ex vivo manipulated intracranial delivery. These therapies have relied on direct injections into the brain, whereas a clinically desirable therapy would involve i.v. infusion of a recombinant enzyme. We previously characterized a recombinant neprilysin that contained a 38-amino acid brain-targeting domain. Recombinant cell lines have been generated expressing this brain-targeted enzyme (ASN12). In this report, we characterize the ASN12 recombinant protein for pharmacology in a mouse as well as efficacy in two APPtg mouse models of AD. The recombinant ASN12 transited to the brain with a t½ of 24 h and accumulated to 1.7% of injected dose at 24 h following i.v. delivery. We examined pharmacodynamics in the tg2576 APPtg mouse with the prion promoter APP695 SWE mutation and in the Line41 mThy1 APP751 mutation mouse. Treatment of either APPtg mouse resulted in reduced Aβ, increased neuronal synapses, and improved learning and memory. In addition, the Line41 APPtg mice showed increased levels of C-terminal neuropeptide Y fragments and increased neurogenesis. These results suggest that the recombinant brain-targeted neprilysin, ASN12, may be an effective treatment for AD and warrant further investigation in clinical trials.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain; Hep G2 Cells; Humans; Mice; Mice, Transgenic; Mutation; Neprilysin; Neurogenesis; Neuropeptide Y; Neuroprotective Agents; Rats; Recombinant Fusion Proteins

Weight loss is a prominent early feature of Alzheimer's disease (AD) that often precedes the cognitive decline and clinical diagnosis. While the exact pathogenesis of AD remains unclear, accumulation of amyloid-β (Aβ) derived from the amyloid precursor protein (APP) in the brain is thought to lead to the neuronal dysfunction and death underlying the dementia. In this study, we examined whether transgenic mice overexpressing the Swedish mutation of APP (Tg2576), recapitulating selected features of AD, have hypothalamic leptin signaling dysfunction leading to early body weight deficits. We found that 3-month-old Tg2576 mice, before amyloid plaque formation, exhibit decreased weight with markedly decreased adiposity, low plasma leptin levels, and increased energy expenditure without alterations in feeding behavior. The expression of the orexigenic neuropeptide Y (NPY) in the hypothalamus to the low leptin state was abnormal at basal and fasting conditions. In addition, arcuate NPY neurons exhibited abnormal electrophysiological responses to leptin in Tg2576 hypothalamic slices or wild-type slices treated with Aβ. Finally, the metabolic deficits worsened as Tg2576 mice aged and amyloid burden increased in the brain. These results indicate that excess Aβ can potentially disrupt hypothalamic arcuate NPY neurons leading to weight loss and a pathologically low leptin state early in the disease process that progressively worsens as the amyloid burden increases. Collectively, these findings suggest that weight loss is an intrinsic pathological feature of Aβ accumulation and identify hypothalamic leptin signaling as a previously unrecognized pathogenic site of action for Aβ.

Topics: Adiposity; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Arcuate Nucleus of Hypothalamus; Brain; Brain Chemistry; Disease Models, Animal; Disease Progression; Fasting; Feeding Behavior; Female; Genes, Reporter; Humans; Hypothalamus; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Neurons; Neuropeptide Y; Patch-Clamp Techniques; Plaque, Amyloid; Weight Loss

BACE1 is the rate-limiting enzyme that cleaves amyloid precursor protein (APP) to produce the amyloid β peptides that accumulate in Alzheimer's disease (AD). BACE1, which is elevated in AD patients and APP transgenic mice, also cleaves the β2-subunit of voltage-gated sodium channels (Navβ2). Although increased BACE1 levels are associated with Navβ2 cleavage in AD patients, whether Navβ2 cleavage occurs in APP mice had not yet been examined. Such a finding would be of interest because of its potential impact on neuronal activity: previous studies demonstrated that BACE1-overexpressing mice exhibit excessive cleavage of Navβ2 and reduced sodium current density, but the phenotype associated with loss of function mutations in either Navβ-subunits or pore-forming α-subunits is epilepsy. Because mounting evidence suggests that epileptiform activity may play an important role in the development of AD-related cognitive deficits, we examined whether enhanced cleavage of Navβ2 occurs in APP transgenic mice, and whether it is associated with aberrant neuronal activity and cognitive deficits. We found increased levels of BACE1 expression and Navβ2 cleavage fragments in cortical lysates from APP transgenic mice, as well as associated alterations in Nav1.1α expression and localization. Both pyramidal neurons and inhibitory interneurons exhibited evidence of increased Navβ2 cleavage. Moreover, the magnitude of alterations in sodium channel subunits was associated with aberrant EEG activity and impairments in the Morris water maze. Together, these results suggest that altered processing of voltage-gated sodium channels may contribute to aberrant neuronal activity and cognitive deficits in AD.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Animals; Aspartic Acid Endopeptidases; Biotinylation; Cognition Disorders; Disease Models, Animal; Electroencephalography; Gene Expression Regulation; Glutamate Decarboxylase; Humans; Maze Learning; Mice; Mice, Transgenic; Mutation; NAV1.1 Voltage-Gated Sodium Channel; Nerve Tissue Proteins; Neurons; Neuropeptide Y; Sodium Channels

Beta-amyloid (Aβ) peptides are secreted from neurons, resulting in extracellular accumulation of Aβ and neurodegeneration of Alzheimer's disease. Because neuronal secretion is fundamental for the release of neurotransmitters, this study assessed the hypothesis that Aβ undergoes co-release with neurotransmitters. Model neuronal-like chromaffin cells were investigated, and results illustrate regulated, co-secretion of Aβ(1-40) and Aβ(1-42) with peptide neurotransmitters (galanin, enkephalin, and NPY) and catecholamine neurotransmitters (dopamine, norepinephrine, and epinephrine). Regulated secretion from chromaffin cells was stimulated by KCl depolarization and nicotine. Forskolin, stimulating cAMP, also induced co-secretion of Aβ peptides with peptide and catecholamine neurotransmitters. These data suggested the co-localization of Aβ with neurotransmitters in dense core secretory vesicles (DCSV) that store and secrete such chemical messengers. Indeed, Aβ was demonstrated to be present in DCSV with neuropeptide and catecholamine transmitters. Furthermore, the DCSV organelle contains APP and its processing proteases, β- and γ-secretases, that are necessary for production of Aβ. Thus, Aβ can be generated in neurotransmitter-containing DCSV. Human IMR32 neuroblastoma cells also displayed regulated secretion of Aβ(1-40) and Aβ(1-42) with the galanin neurotransmitter. These findings illustrate that Aβ peptides are present in neurotransmitter-containing DCSV, and undergo co-secretion with neuropeptide and catecholamine neurotransmitters that regulate brain functions.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Animals; Catecholamines; Cattle; Cells, Cultured; Chromaffin Cells; Colforsin; Cyclic AMP; Dopamine; Enkephalins; Epinephrine; Galanin; Ganglionic Stimulants; Humans; Neuroblastoma; Neurons; Neuropeptide Y; Neuropeptides; Neurotransmitter Agents; Nicotine; Norepinephrine; Peptide Fragments; Secretory Vesicles

At advanced stages of Alzheimer's disease, cognitive dysfunction is accompanied by severe alterations of hippocampal circuits that may largely underlie memory impairments. However, it is likely that anatomical remodeling in the hippocampus may start long before any cognitive alteration is detected. Using the well-described Tg2576 mouse model of Alzheimer's disease that develops progressive age-dependent amyloidosis and cognitive deficits, we examined whether specific stages of the disease were associated with the expression of anatomical markers of hippocampal dysfunction. We found that these mice develop a complex pattern of changes in their dentate gyrus with aging. Those include aberrant expression of neuropeptide Y and reduced levels of calbindin, reflecting a profound remodeling of inhibitory and excitatory circuits in the dentate gyrus. Preceding these changes, we identified severe alterations of adult hippocampal neurogenesis in Tg2576 mice. We gathered converging data in Tg2576 mice at young age, indicating impaired maturation of new neurons that may compromise their functional integration into hippocampal circuits. Thus, disruption of adult hippocampal neurogenesis occurred before network remodeling in this mouse model and therefore may account as an early event in the etiology of Alzheimer's pathology. Ultimately, both events may constitute key components of hippocampal dysfunction and associated cognitive deficits occurring in Alzheimer's disease.

Topics: Aging; Alzheimer Disease; Animals; Biomarkers; Calbindin 1; Cell Count; Cell Movement; Dentate Gyrus; Disease Models, Animal; Disease Progression; Gene Expression Regulation; Hippocampus; Male; Mice; Mice, Transgenic; Neurogenesis; Neurons; Neuropeptide Y; Time Factors

Levels of educational and occupational attainment, as components of cognitive reserve, may modify the relationship between the pathological hallmarks and cognition in Alzheimer's disease (AD). We examined whether exposure of a Tg2576 transgenic mouse model of AD to environmental enrichment (EE) at a specific period during the amyloidogenic process favored the establishment of a cognitive reserve. We found that exposure to EE during early adulthood of Tg2576 mice--before amyloidogenesis has started--reduced the severity of AD-related cognitive deficits more efficiently than exposure later in life, when the pathology is already present. Interestingly, early-life exposure to EE, while slightly reducing forebrain surface covered by amyloid plaques, did not significantly impact aberrant inhibitory remodeling in the hippocampus of Tg2576 mice. Thus, transient early-life exposure to EE exerts long-lasting protection against cognitive impairment during AD pathology. In addition, these data define the existence of a specific life time frame during which stimulatory activity most efficiently builds a cognitive reserve, limiting AD progression and favoring successful aging.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloidosis; Analysis of Variance; Animals; Calbindins; Cognition Disorders; Disease Models, Animal; Environment; Exploratory Behavior; Humans; Maze Learning; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Neuropeptide Y; Recognition, Psychology; S100 Calcium Binding Protein G; Spatial Behavior; Statistics, Nonparametric

Using in vitro models of Alzheimer's disease (AD), we found that the toxic effects of amyloid beta 25-35 (Aβ(25-35)) on the neurotrophin brain-derived neurotrophic factor (BDNF) were counteracted by pre-incubation with neuropeptide Y (NPY), a neuropeptide expressed within the central nervous system. Nonetheless, the mechanism of action of NPY on BDNF neuronal production in the presence of Aβ is not known. BDNF expression might be directly regulated by microRNA (miRs), small non-coding DNA fragments that regulate the expression of target genes. Thus, there is the possibility that miRs alterations are present in AD-affected neurons and that NPY influences miR expression. To test this hypothesis, we exposed NPY-pretreated primary rat cortical neurons to Aβ(25-35) and measured miR-30a-5p (a member of the miR-30a family involved in BDNF tuning expression) and BDNF mRNA and protein expression after 24 and 48 h. Our results demonstrated that pre-treatment with NPY decreased miR-30a-5p expression and increased BDNF mRNA and protein expression at 24 and 48 h of incubation with Aβ. Therefore, this study demonstrates that NPY modulates BDNF and its regulating microRNA miR-30a-5p in opposite direction with a mechanism that possibly contributes to the neuroprotective effect of NPY in rat cortical neurons exposed to Aβ.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Base Sequence; Brain-Derived Neurotrophic Factor; Cells, Cultured; Cerebellar Cortex; Gene Expression Regulation; MicroRNAs; Molecular Sequence Data; Neurons; Neuropeptide Y; Neuroprotective Agents; Peptide Fragments; Rats; Rats, Wistar

We investigated the role of endogenous neuropeptide Y (NPY) system in nicotine-mediated improvement of learning and memory in rat model of Alzheimer's disease (AD). Intracerebroventricular (icv) colchicine treatment induced AD-like condition in rats and showed increased escape latency (decreased learning), and amnesic condition in probe test in Morris water maze. In these rats, nicotine (0.5mg/kg, intraperitoneal), NPY (100 ng/rat, icv) or NPY Y1 receptor agonist [Leu(31), Pro(34)]-NPY (0.04 ng/rat, icv) decreased escape latency by 54.76%, 55.81% and 44.18%, respectively, on day 4 of the acquisition. On the other hand, selective NPY Y1 receptor antagonist, BIBP3226 (icv) produced opposite effect (44.18%). In the probe test conducted at 24h time point, nicotine, NPY or [Leu(31), Pro(34)]-NPY increased the time spent by 72.72%, 44.11% and 26.47%, respectively; while BIBP3226 caused reduction (8.82%). It seems that while NPY or [Leu(31), Pro(34)]-NPY potentiated, BIBP3226 attenuated the learning and memory enhancing effects of nicotine. Brains of colchicine treated rats showed significant reduction in NPY-immunoreactivity in the nucleus accumbens shell (cells 62.23% and fibers 50%), bed nucleus of stria terminalis (fibers 71.58%), central nucleus of amygdala (cells 74.33%), arcuate nucleus (cells 70.97% and fibers 69.65%) and dentate gyrus (cells 58.54%). However, in these rats nicotine treatment for 4 days restored NPY-immunoreactivity to the control level. We suggest that NPY, perhaps acting via NPY Y1 receptors, might interact with the endogenous cholinergic system and play a role in improving the learning and memory processes in the rats with AD-like condition.

Topics: Alzheimer Disease; Amygdala; Analysis of Variance; Animals; Arcuate Nucleus of Hypothalamus; Arginine; Colchicine; Dentate Gyrus; Disease Models, Animal; Escape Reaction; Learning; Male; Maze Learning; Memory; Neuropeptide Y; Nicotine; Nicotinic Agonists; Nucleus Accumbens; Rats; Rats, Sprague-Dawley; Receptors, Neuropeptide Y; Septal Nuclei

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by brain accumulation of amyloid-β peptide and neurofibrillary tangles, which are believed to initiate a pathological cascade that results in progressive impairment of cognitive functions and eventual neuronal death. To obtain a mouse model displaying the typical AD histopathology of amyloidosis and tauopathy, we generated a triple-transgenic mouse line (TauPS2APP) by overexpressing human mutations of the amyloid precursor protein, presenilin2 and tau genes. Stereological analysis of TauPS2APP mice revealed significant neurodegeneration of GABAergic septo-hippocampal projection neurons as well as their target cells, the GABAergic hippocampal interneurons. In contrast, the cholinergic medial septum neurons remained unaffected. Moreover, the degeneration of hippocampal GABAergic interneurons was dependent on the hippocampal subfield and interneuronal subtype investigated, whereby the dentate gyrus and the NPY-positive interneurons, respectively, were most strongly affected. Neurodegeneration was also accompanied by a change in the mRNA expression of markers for inhibitory interneurons. In line with the loss of inhibitory neurons, we observed functional changes in TauPS2APP mice relative to WT mice, with strongly enhanced long-term potentiation in the medial-perforant pathway input to the dentate gyrus, and stereotypic hyperactivity. Our data indicate that inhibitory neurons are the targets of neurodegeneration in a mouse model of amyloidosis and tauopathy, thus pointing to a possible role of the inhibitory network in the pathophysiological and functional cascade of Alzheimer's disease.

Topics: Alzheimer Disease; Amyloidosis; Animals; Cholinergic Neurons; Disease Models, Animal; GABAergic Neurons; Hippocampus; Interneurons; Long-Term Potentiation; Mice; Mice, Transgenic; Neuropeptide Y; Presenilin-2; Septal Nuclei; tau Proteins; Tauopathies

The tight coupling between neuronal activity and the local increase of blood flow termed neurovascular coupling is essential for normal brain function. This mechanism of regulation is compromised in Alzheimer's Disease (AD). In order to determine whether a purely vascular dysfunction or a neuronal alteration of blood vessels diameter control could be responsible for the impaired neurovascular coupling observed in AD, blood vessels reactivity in response to different pharmacological stimulations was examined in double transgenic APPxPS1 mice model of AD. Blood vessels movements were monitored using infrared videomicroscopy ex vivo, in cortical slices of 8 month-old APPxPS1 and wild type (WT) mice. We quantified vasomotor responses induced either by direct blood vessel stimulation with a thromboxane A2 analogue, the U46619 (9,11-dideoxy-11a,9a-epoxymethanoprostaglandin F2α) or via the stimulation of interneurons with the nicotinic acetylcholine receptor (nAChRs) agonist DMPP (1,1-Dimethyl-4- phenylpiperazinium iodide). Using both types of stimulation, no significant differences were detected for the amplitude of blood vessel diameter changes between the transgenic APPxPS1 mice model of AD and WT mice, although the kinetics of recovery were slower in APPxPS1 mice. We find that activation of neocortical interneurons with DMPP induced both vasodilation via Nitric Oxide (NO) release and constriction via Neuropeptide Y (NPY) release. However, we observed a smaller proportion of reactive blood vessels following a neuronal activation in transgenic mice compared with WT mice. Altogether, these results suggest that in this mouse model of AD, deficiency in the cortical neurovascular coupling essentially results from a neuronal rather than a vascular dysfunction.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Area Under Curve; Blood Vessels; Brain; Cerebrovascular Circulation; Dimethylphenylpiperazinium Iodide; Disease Models, Animal; Ganglionic Stimulants; Humans; In Vitro Techniques; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Neuropeptide Y; Presenilin-1; Vasoconstrictor Agents; Vasodilation

High levels of Aβ impair neuronal function at least in part by disrupting normal synaptic transmission and causing dysfunction of neural networks. This network dysfunction includes abnormal synchronization of neuronal activity resulting in epileptiform activity. Over time, this aberrant network activity can lead to the depletion of calcium-dependent proteins, such as calbindin, Fos, and Arc, and compensatory inhibitory remodeling of hippocampal circuits, including GABAergic sprouting and ectopic expression of the inhibitory neuropeptide Y (NPY) in dentate granule cells. Here we present detailed protocols for detecting and quantifying these alterations in mouse models of Alzheimer's disease (AD) by immunohistochemistry. These methods are useful as surrogate measures for detecting chronic aberrant network activity in models of AD and epilepsy. In addition, since we have found that the severity of these changes relates to the degree of Aβ-dependent cognitive impairments, the protocols are useful for quantifying biomarkers of cognitive impairment in mouse models of AD.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Biomarkers; Cognition Disorders; Hippocampus; Humans; Immunohistochemistry; In Vitro Techniques; Mice; Mice, Transgenic; Neuropeptide Y

The endopeptidase neprilysin (NEP) is a major amyloid-beta (Abeta) degrading enzyme and has been implicated in the pathogenesis of Alzheimer's disease. Because NEP cleaves substrates other than Abeta, we investigated the potential role of NEP-mediated processing of neuropeptides in the mechanisms of neuroprotection in vivo. Overexpression of NEP at low levels in transgenic (tg) mice affected primarily the levels of neuropeptide Y (NPY) compared with other neuropeptides. Ex vivo and in vivo studies in tg mice and in mice that received lentiviral vector injections showed that NEP cleaved NPY into C-terminal fragments (CTFs), whereas silencing NEP reduced NPY processing. Immunoblot and mass spectrometry analysis showed that NPY 21-36 and 31-36 were the most abundant fragments generated by NEP activity in vivo. Infusion of these NPY CTFs into the brains of APP (amyloid precursor protein) tg mice ameliorated the neurodegenerative pathology in this model. Moreover, the amidated NPY CTFs protected human neuronal cultures from the neurotoxic effects of Abeta. This study supports the possibility that the NPY CTFs generated during NEP-mediated proteolysis might exert neuroprotective effects in vivo. This function of NEP represents a unique example of a proteolytic enzyme with dual action, namely, degradation of Abeta as well as processing of NPY.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Arginine; Benzazepines; Cells, Cultured; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Gene Expression Regulation; Genetic Vectors; Humans; Mice; Mice, Transgenic; Neprilysin; Nerve Degeneration; Nerve Growth Factors; Neurons; Neuropeptide Y; Peptide Fragments; Receptors, Neuropeptide Y

In Alzheimer's disease, toxic soluble and insoluble forms of amyloid beta (Abeta) cause synaptic dysfunction and neuronal loss. Given its potential role in producing a toxic host microenvironment for transplanted donor stem cells, we investigated the interaction between Abeta and proliferation, survival, and differentiation of bone marrow-derived mesenchymal stem cells (BM-MSC) in culture.. We used BM-MSC that had been isolated from mouse bone marrow and cultured, and we also assessed relevant reaction mechanisms using gene microarray, immunocytochemistry, and inhibitors of potential signalling molecules, such as mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK)1/2 and tyrosine protein kinase.. Interestingly, we found that treatment with aggregated (1-40 or 1-42) and oligomeric (1-42) Abeta promoted neuronal-like differentiation of BM-MSC without toxic effects. This was not dependent on soluble factors released from BM-MSC progeny nor solely on formation of Abeta fibrils. The effect of Abeta is mediated by G-protein coupled receptors, neuropeptide Y1 (NPY1R) and serotonin (5-hydroxytryptamine) receptor 2B, via phosphatidylinositol-3-OH kinase-dependent activation of the MAPK/ERK1/2. Our results lend support to the idea that reciprocal donor stem cell-host interactions may promote a regenerative response that can be exploited by epigenetic modulation of NPY/serotonergic gene expression, for stem cell therapy, in Alzheimer's disease.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Apoptosis; Bone Marrow Cells; Cell Differentiation; Cell Division; Cell Survival; Cells, Cultured; Dynamins; MAP Kinase Signaling System; Mesenchymal Stem Cells; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Neuronal Plasticity; Neuropeptide Y; Peptide Fragments; Phosphatidylinositol 3-Kinases; Receptor, Serotonin, 5-HT2B; Receptors, Neuropeptide Y

Alzheimer's disease (AD) is characterized by three primary pathologies in the brain: amyloid plaques, neurofibrillary tangles, and neuron loss. Mouse models have been useful for studying components of AD but are limited in their ability to fully recapitulate all pathologies. We crossed the APPSwDI transgenic mouse, which develops amyloid beta (Abeta)-protein deposits only, with a nitric oxide synthase 2 (NOS2) knock-out mouse, which develops no AD-like pathology. APPSwDI/NOS2(-/-) mice displayed impaired spatial memory compared with the APPSwDI mice, yet they have unaltered levels of Abeta. APPSwDI mice do not show tau pathology, whereas APPSwDI/NOS2(-/-) mice displayed extensive tau pathology associated with regions of dense microvascular amyloid deposition. Also, APPSwDI mice do not have any neuron loss, whereas the APPSwDI/NOS2(-/-) mice have significant neuron loss in the hippocampus and subiculum. Neuropeptide Y neurons have been shown to be particularly vulnerable in AD. These neurons appear to be particularly vulnerable in the APPSwDI/NOS2(-/-) mice as we observe a dramatic reduction in the number of NPY neurons in the hippocampus and subiculum. These data show that removal of NOS2 from an APP transgenic mouse results in development of a much greater spectrum of AD-like pathology and behavioral impairments.

Topics: Alzheimer Disease; Animals; Cerebral Amyloid Angiopathy; Disease Models, Animal; Disease Progression; Hippocampus; Immunohistochemistry; Memory Disorders; Mice; Mice, Transgenic; Neurons; Neuropeptide Y; Nitric Oxide Synthase Type II

A typical paradigm in the investigation of complex human disease is to assess the effects of cis-regulatory polymorphisms implicated in association studies on transcription in cellular expression systems. Evidence from in vitro transfection studies is often assumed to be sufficient evidence for the in vivo functional importance of a polymorphism in the context of human disease, even though many confounding effects (e.g. temporal regulation, tissue specificity, genetic background) are not considered. In this study, we evaluate this assumption directly by examining the translation of in vitro results on allele-specific expression to an in vivo system using four genes that have been well documented through reporter assays to have promoter polymorphisms affecting transcription level: monoamine oxidase A (MAOA), neuropeptide Y (NPY), endothelial nitric oxide synthase (NOS3), and prodynorphin (PDYN). In our study, MAOA was found to have large allelic imbalances, which indicates that there is in vivo variation in the expression of this gene. However, the imbalances observed were not correlated with genotype at the putatively functional polymorphism. PDYN, NOS3 and NPY did not have large allelic imbalances. Overall, there was no statistically significant effect of these polymorphisms on expression level as measured by imbalance ratios in any of these genes. These results suggest that the functional effects of a polymorphism on gene expression may be more complicated and context dependent than is often assumed and also imply that the use of cell-based expression studies to support the role of such polymorphisms in disease etiology should be treated with caution.

Topics: Aged; Aged, 80 and over; Allelic Imbalance; Alzheimer Disease; Brain; Enkephalins; Female; Gene Expression; Genes, Reporter; Genetic Predisposition to Disease; Genetic Variation; Genotype; Humans; Male; Monoamine Oxidase; Neuropeptide Y; Nitric Oxide Synthase Type III; Polymorphism, Genetic; Promoter Regions, Genetic; Protein Precursors

Alzheimer's disease is a devastating neurological disorder. The role of hyperexcitability in the disease's cognitive decline is not completely understood. In this issue of Neuron, Palop et al. report both limbic seizures and presumed homeostatic responses to seizures in an animal model of Alzheimer's.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Cognition Disorders; Dentate Gyrus; Disease Models, Animal; Epilepsy; Homeostasis; Humans; Mutation; Neural Inhibition; Neuropeptide Y

Neuropeptide Y (NPY) is a neurotransmitter expressed in the central nervous system and involved in learning and memory. The NPY L7P polymorphism has been associated with altered cholesterol levels in obese patients. Since altered cholesterol metabolism is also involved in Alzheimer's disease (AD), the effects of two NPY polymorphisms (L7P and IVS1-100 T/G) on CSF and plasma cholesterol and 24S-hydroxycholesterol were investigated in AD patients and non-demented controls. Furtheremore, the effect of both NPY polymorphisms on the risk of AD was studied. The NPY IVS1-100 T/G polymorphism influenced CSF levels of cholesterol, whereas CSF and plasma levels of 24S-hydroxycholesterol and plasma cholesterol were not altered by genotype. NPY L7P polymorphism did not influence CSF or plasma cholesterol or 24S-hydroxycholesterol. Both NPY polymorphisms did not influence the risk of AD. Our data support the observation, that NPY polymorphisms might influence cholesterol metabolism, but might not act as major risk factor in AD.

Topics: Aged; Alzheimer Disease; Exons; Female; Genetic Predisposition to Disease; Humans; Hydroxycholesterols; Male; Middle Aged; Neuropeptide Y; Polymorphism, Genetic; Risk Factors

At advanced stages, Alzheimer's disease (AD) is characterized by an extensive neuronal loss. However, the early neurodegenerative deficiencies have not been yet identified. Here we report an extensive, selective and early neurodegeneration of the dendritic inhibitory interneurons (oriens-lacunosum moleculare, O-LM, and hilar perforant path-associated, HIPP, cells) in the hippocampus of a transgenic PS1xAPP AD model. At 6 months of age, from 22 different pre- and postsynaptic mRNA markers tested (including GABAergic, glutamatergic and cholinergic markers), only the expression of somatostatin (SOM) and NPY neuropeptides (O-LM and HIPP markers) displayed a significant decrease. Stereological cell counting demonstrated a profound diminution (50-60%) of SOM-immunopositive neurons, preceding the pyramidal cell loss in this AD model. SOM population co-expressing NPY was the most damaged cell subset. Furthermore, a linear correlation between SOM and/or NPY deficiency and Abeta content was also observed. Though the molecular mechanism of SOM neuronal loss remains to be determined, these findings might represent an early hippocampal neuropathology. Therefore, SOM and NPY neuropeptides could constitute important biomarkers to assess the efficacy of potential early AD treatments.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Blotting, Western; gamma-Aminobutyric Acid; Hippocampus; Interneurons; Mice; Mice, Transgenic; Neuropeptide Y; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Somatostatin

In the central nervous system, several neuropeptides are believed to be involved in the pathophysiology of Alzheimer's disease (AD). Indeed, previous studies have documented that glucagon-like peptide 1 (GLP-1) possesses neurotropic properties and can reduce amyloid-beta peptide levels in the brain in vivo. Moreover, the concentrations of neuropeptide Y (NPY) seem to be altered in the cerebrospinal fluid of patients with AD and in subjects with major depression. Finally, among the modifications induced by aging, a dysregulation of the ghrelin-growth hormone (GH) system has been reported.. We investigated the plasma concentrations of these neuropeptides in 14 subjects with AD. Data obtained from these patients were compared with data from an age- and weight-matched healthy group.. No significant differences were found between the two groups in relation to plasma levels of GLP-1, NPY, ghrelin and GH. Peripheral NPY concentrations were positively correlated with ghrelin levels in both groups, and with plasma GLP-1 concentration only in controls.. On the basis of our results, peripheral levels of these neuropeptides seem not to serve as biochemical markers of AD.

Topics: Aged; Aged, 80 and over; Aging; Alzheimer Disease; Biomarkers; Female; Ghrelin; Glucagon-Like Peptide 1; Human Growth Hormone; Humans; Neuropeptide Y; Peptide Hormones

Alzheimer's disease (AD) and frontotemporal dementia (FTD) are two prevalent neurodegenerative disorders for which the causes are unknown, except in rare familial cases. Several changes in neuropeptide levels as measured by radioimmunoassay (RIA) have been observed in these illnesses. Somatostatin (SOM) levels in cerebrospinal fluid (CSF) are consistently decreased in AD and FTD. Neuropeptide Y (NPY) levels are decreased in AD, but normal in FTD. Galanin (GAL) levels increase with the duration of illness in AD patients. The majority of studies of neuropeptides in CSF have not been verified by HPLC. The observed decrease in a neuropeptide level as measured by RIA may therefore reflect an altered synthesis or extracellular processing, resulting in neuropeptide fragments that may or may not be detected by RIA. Matrix-assisted laser desorption time-of-flight mass spectrometry (MALDI-MS) has been shown to be a powerful technique in the analysis of biological materials without any pre-treatment, by detecting peptides and proteins at a specific mass-to-charge (m/z) ratio. We studied the processing of the neuropeptides NPY, NPY, SOM and GAL in the cerebrospinal fluid of patients with AD (n = 3), FTD (n = 3) and controls (n = 2) using MALDI-MS. We found that considerable inter-individual variability exists in the rate of neuropeptide metabolism in CSF, as well as the number of peptide fragments formed. Certain patients showed differences in the processing of specific neuropeptides, relative to other patients and controls. This analysis of the metabolic processing of neuropeptides in CSF yielded a large amount of data for each individual studied. Further studies are required to determine the changes in neuropeptide processing that can be associated with AD and FTD. With further investigations using MALDI-MS analysis, it may be possible to identify a neuropeptide fragment or processing enzyme that can be correlated to these disease states.

Topics: Alzheimer Disease; Case-Control Studies; Dementia; Female; Galanin; Humans; Male; Middle Aged; Neuropeptide Y; Somatostatin; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization

Both apolipoprotein E varepsilon4 allele (APOE varepsilon4) and neuropeptide Y (NPY) Pro(7)-variant have been reported to be associated with higher serum levels of total and LDL cholesterol. Since APOE varepsilon4 allele is also a major risk factor for the development of Alzheimer's disease (AD) and the genetic polymorphism of NPY has not previously been studied in dementing disorders, we have examined whether a novel polymorphism in a signal peptide of NPY gene is associated with AD alone or in combination with APOE varepsilon4. A total of 125 sporadic AD cases and 110 control individuals from Finland were genotyped for APOE and NPY genes using the polymerase chain reaction and restriction enzyme analysis. The APOE varepsilon4 allele frequency was significantly increased in the AD group compared with controls as expected. Instead, no significant differences were found between sporadic AD patients and controls either in the NPY genotype or allele frequencies or in combination with the APOE varepsilon4 allele. We conclude that APOE varepsilon4 allele represents a strong predictor of risk for AD.

Topics: Aged; Alleles; Alzheimer Disease; Apolipoproteins E; Female; Genotype; Humans; Leucine; Male; Neuropeptide Y; Polymorphism, Single Nucleotide; Proline; Protein Sorting Signals

Impairment of the basal forebrain cholinergic system is an important change in the brains of Alzheimer's disease patients. Various neurotoxins have been used to achieve this in animal models. In this study the effects of chemical lesions by ibotenic acid (IBO), a glutamate analogue and by 192 IgG-saporin, a highly specific immunotoxin against cholinergic neurons, were investigated. The toxins were delivered stereotaxically into the brains of young Sprague-Dawley rats which were later sacrificed by decapitation. Choline acetyltransferase (ChAT) activity was measured by radioenzymatic assay and substance P (SP), neuropeptide Y (NPY) and somatostatin (SOM) levels by radioimmunoassay. Decreased ChAT and SOM levels were observed in the cortex and the hippocampus in both experiments. Cortical SP levels were increased after IBO lesions but were unaffected after 192 IgG-saporin lesions. NPY levels remained unchanged in both experiments. The results indicate that there were specific changes in neuropeptide contents in the cortex and hippocampus in response to cholinergic damage in the rat brain.

Topics: Alzheimer Disease; Animals; Antibodies, Monoclonal; Behavior, Animal; Brain Chemistry; Cerebral Cortex; Choline O-Acetyltransferase; Cholinergic Agents; Cholinergic Fibers; Excitatory Amino Acid Agonists; Hippocampus; Ibotenic Acid; Immunotoxins; Male; Maze Learning; N-Glycosyl Hydrolases; Neuropeptide Y; Rats; Rats, Sprague-Dawley; Ribosome Inactivating Proteins, Type 1; Saporins; Somatostatin; Substance P

Nucleation-dependent polymerization of beta-amyloid peptide, the major component of plaques in patients with Alzheimer's disease, is significantly accelerated by crosslinking through Advanced Glycation End-products (AGEs) in vitro. During the polymerization process, both nucleus formation and aggregate growth are accelerated by AGE-mediated crosslinking. Formation of the AGE-crosslinked amyloid peptide aggregates could be attenuated by the AGE-inhibitors Tenilsetam, aminoguanidine and carnosine. These experimental data, and clinical studies, reporting a marked improvement in cognition and memory in Alzheimer's disease patients after Tenilsetam treatment, suggest that AGEs might play an important role in the etiology or progression of the disease. Thus AGE-inhibitors may generally become a promising drug class for the treatment of Alzheimer's disease.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Benzothiazoles; Carnosine; Cognition; Cross-Linking Reagents; Fructose; Glycation End Products, Advanced; Guanidines; Humans; Memory; Neuropeptide Y; Particle Size; Peptide Fragments; Piperazines; Protein Structure, Secondary; Solubility; Temperature; Thiazoles; Thiophenes

The association between Alzheimer caregiving and natural killer (NK) cell activity and basal plasma levels of adrenocorticotropic hormone (ACTH), cortisol, beta-endorphin, prolactin, epinephrine, norepinephrine, and neuropeptide Y was determined in 100 spousal Alzheimer caregivers and 33 age- and gender-comparable control volunteers upon intake into a study of the psychological and physiologic impact of caregiving. The relationship between these physiologic measures and individual characteristics such as age, gender, medical status, severity of stress, severity of depressive symptoms, and caregiver burden was tested. In addition, the association between NK activity and alterations of the neuroendocrine measures was investigated. As compared to controls, the Alzheimer caregivers had similar levels of NK activity and of basal plasma neuroendocrine hormones and sympathetic measures. While older age and male gender status were associated with increased levels of ACTH, neither medical caseness, severity of life stress, nor severity of depressive symptoms was associated with alterations in any of the multiple physiologic domains. Classification of Alzheimer caregiver burden identified caregivers who were mismatched in terms of the amount of care they were required to provide and the amount of respite time received. The mismatched caregivers had significantly higher basal plasma ACTH but no change in other physiological measures, as compared to non-mismatched caregivers. NK activity was negatively correlated with plasma levels of neuropeptide Y but not with any of the other neuroendocrine measures. Based on this cross-sectional evaluation of NK activity and neuroendocrine and sympathetic measures, we conclude that most Alzheimer caregivers do not show evidence of altered basal physiology.

Topics: Adaptation, Psychological; Adrenocorticotropic Hormone; Adult; Aged; Alzheimer Disease; Arousal; beta-Endorphin; Caregivers; Cost of Illness; Depression; Epinephrine; Female; Humans; Hydrocortisone; Individuality; Killer Cells, Natural; Longitudinal Studies; Male; Middle Aged; Neuropeptide Y; Norepinephrine; Pituitary-Adrenal System; Prolactin; Psychoneuroimmunology; Stress, Psychological; Sympathetic Nervous System

Much is known about modular organization in the cerebral cortex, but this knowledge is skewed markedly toward primary sensory areas, and in fact, it has been difficult to demonstrate elsewhere. In this report, we test the hypothesis that a unique form of modules exists in the entorhinal area of the human cortex (Brodmann's area 28). We examined this issue using classic cyto- and myeloarchitectonic stains, immunolabeling for various neurochemicals, and histochemistry for certain enzymes. The findings reveal that the entorhinal cortex in the human is formed by a mosaic of cellular aggregates whose most conspicuous elements are the cell islands of layer II and myelinated fibers around the cell islands, the disposition of glutamic acid decarboxylase-positive neurons and processes, cytochrome oxidase staining, and the pattern of cholinergic afferent fibers. The neuropathology of Alzheimer's disease cases highlights the modules, but inversely so, by destroying their features. The findings are of interest because 1) anatomically defined modules are shown to be present in areas other than the sensory and motor cortices, 2) the modules are morphological entities likely to reflect functions of the entorhinal cortex, and 3) the destruction of entorhinal cortex modules may account disproportionately for the severity of memory impairments in Alzheimer's disease.

Topics: Acetylcholinesterase; Adolescent; Adult; Aged; Aged, 80 and over; Alzheimer Disease; Child; Child, Preschool; Dementia; Electron Transport Complex IV; Glutamate Decarboxylase; Glutaminase; Hippocampus; Histocytochemistry; Humans; Immunohistochemistry; Middle Aged; Neurons; Neuropeptide Y; Parvalbumins; Reference Values; Somatostatin

Neuropeptide Y (NPY) has been shown to be involved in the control of several neuroendocrine functions. Moreover, in animal models, NPY produces behavioral effects that are similar to those induced by anxiolytics. We studied NPY-like immunoreactivity (NPY-LI) in cerebrospinal fluid (CSF) in two primary degenerative dementias, Alzheimer disease (AD, n = 34) and frontotemporal dementia (FTD, n = 22) and correlated the CSF NPY-LI levels with clinical characteristics, as rated with the Organic Brain Syndrome scale. There were significant correlations between NPY-LI and such clinical items as suspiciousness, anxiousness, restlessness-agitation, and irritability in both AD and FTD. AD patients, but not FTD patients, showed a significant negative correlation between NPY-LI and duration of the disease. Thus, the study found significant correlations between CSF NPY-LI and emotional symptoms and behavior in organic dementia.

Topics: Adult; Aged; Aggression; Alzheimer Disease; Anxiety; Dementia; Female; Humans; Male; Middle Aged; Neuropeptide Y; Paranoid Disorders; Radioimmunoassay

Most of the neurons in the subcortical white matter of the adult cerebrum are remnants of the transient subplate cortex which appears during early cortical development. The peptidergic neurons in the subcortical white matter, beneath the striate cortex were examined qualitatively and qualitatively with immunohistochemistry for substance P, cholecystokinin, somatostatin and neuropeptide Y in seven control patients and eight patients with Alzheimer's disease. The different peptidergic subcortical neurons still persisted in normal aging. In Alzheimer's disease, however, the substance P- and somatostatin-immunoreactive neurons were decreased in numbers and showed degenerative changes.

Topics: Aged; Aged, 80 and over; Aging; Alzheimer Disease; Cholecystokinin; Female; Humans; Immunohistochemistry; Male; Middle Aged; Neurons; Neuropeptide Y; Neuropeptides; Somatostatin; Substance P; Visual Cortex

Tau protein concentrations were measured in the CSF of 23 patients with dementia of the Alzheimer type (DAT), 36 patients with multi-infarct dementia (MID), and 23 control subjects. Tau protein concentrations were significantly higher in patients with DAT than in controls (P < 0.001) and patients with MID (P < 0.001). A significantly positive correlation between CSF tau protein and glucose concentrations (r = 0.79, P < 0.001) and evolution of disease (r = 0.47, P < 0.05), and a negative correlation with Folstein's mental state examination test (r = -0.73, P < 0.001) were found in patients with DAT.

Topics: Aged; Alzheimer Disease; Enzyme-Linked Immunosorbent Assay; Female; Humans; Male; Middle Aged; Neuropeptide Y; Somatostatin; Substance P; tau Proteins

We established the cartography of 11 exo- and endopeptidases in the frontal and parietal cortices and in the cerebellum of brains of patients diagnosed with a senile dementia of the Alzheimer's type (SDAT). Comparison with those of four subjects who had died without known neurologic or psychiatric illness indicated that there existed a region-specific alteration of the peptidase contents in the disease. In the frontal area of SDAT brains, postproline dipeptidyl aminopeptidase and aminopeptidase M activities were significantly reduced. In the parietal cortex of SDAT brain, activities of three additional endopeptidases--angiotensin-converting enzyme, proline endopeptidase, and endopeptidase 24.15--were also drastically reduced. In contrast, the cerebellum displayed a set of proteolytic activities that remained unaffected in SDAT brain. The putative influence of the disease on the catabolic fates of neurotensin, neuropeptide Y, and somatostatin(1-14) was investigated. Neurotensin was catabolized at identical rates in the frontal and parietal cortices in nondemented and SDAT brains. In contrast, neuropeptide Y metabolism was slowed down in SDAT brains in the frontal but not in the parietal cortex. Finally, the degradation velocities of somatostatin(1-14) were lowered in both cortical areas of SDAT brains. It is interesting that, by means of specific peptidase inhibitors, we demonstrated that endopeptidase 24.15 participated in somatostatin(1-14) inactivation in the parietal but not in the frontal cortex. It is suggested that the lowering of the rate of somatostatin(1-14) inactivation in the parietal cortex of SDAT brains likely results from the depletion of endopeptidase 24.15 in this brain region.

Topics: Aged; Alzheimer Disease; Cerebellum; Cerebral Cortex; Endopeptidases; Exopeptidases; Female; Humans; Neuropeptide Y; Neuropeptides; Neurotensin; Peptide Hydrolases; Reference Values; Somatostatin

Neuropeptide Y (NPY)-containing neurons are depleted in the cortices of individuals with Alzheimer disease (AD), yet spared in the striatum of patients with Huntington chorea. It is unknown whether this neuronal phenotype is inherently susceptible to the neurodegenerative processes that are a hallmark of AD. To study this question, the murine trisomy 16 model of Down syndrome and Alzheimer disease was investigated. Since trisomic fetuses die in utero, studies were carried out on primary cultures of dissociated cortical neurons. These were prepared from 15-d gestational trisomy 16 fetuses and their littermate euploid controls, and examined by immunocytochemical staining for neuropeptide Y at 7 and 12 d in vitro. Trisomy 16 neurons were also grown on euploid glial carpets, whereas euploid neurons were grown on trisomic glia. The results demonstrate a significant increase in the number of NPY neurons and a stunting in the dendritic arbor of these neurons in trisomic vs euploid cortex. Both of these parameters could be normalized by direct contact with euploid glia. When euploid cortex was plated on trisomic glia, the number of NPY neurons and their morphology were altered so that they began to resemble trisomic NPY cortical neurons. These results indicate a dysregulation of NPY neuronal expression and differentiation in trisomy 16 cortex that are modifiable by interaction with euploid glia and imply an abnormal trophic (glial) environment in trisomic cortex.

Topics: Alzheimer Disease; Animals; Cell Differentiation; Cerebral Cortex; Disease Models, Animal; Down Syndrome; Female; Male; Mice; Mice, Inbred C57BL; Neuroglia; Neuronal Plasticity; Neurons; Neuropeptide Y; Trisomy

Alz-50 is a monoclonal antibody raised against ventral forebrain tissue from patients with Alzheimer's disease (AD). It was originally believed that the antigen recognized by Alz-50 was only found in degenerating neurons. However, recent studies indicate that Alz-50 stains neurons in a limited but specific distribution in normal brains throughout life. As the antigen recognized by Alz-50 in normal brains may give some insight into the AD degenerative process, we characterized Alz-50 staining in the normal ovine striatum using immunoblots and immunocytochemistry at the light and electron microscope levels. We then compared the Alz-50 staining pattern with those of NADPH diaphorase histochemistry and immunocytochemistry using antisera against several neuropeptides, Alzheimer-related proteins, and heat-shock proteins. Western blot analysis indicated that the epitope recognized by Alz-50 in the normal sheep brain is on the microtubule-associated protein tau, and preadsorbing Alz-50 with a peptide corresponding to the amino terminus of the tau molecule eliminated staining. Alz-50 labeled a single population of cells in the ovine striatum, the medium aspiny neurons. At the light microscope level, the granular staining pattern closely resembled Alz-50 immunoreactive neurons in the normal human striatum and in cells undergoing early degeneration in AD. Alz-50 immunoreactive neurons stained immunocytochemically with antisera against somatostatin, neuropeptide Y, and histochemically for NADPH diaphorase. These cells were morphologically characterized by smooth dendrites, elaborate local axonal plexuses, and indented nuclei with filamentous inclusions. Ultrastructurally, Alz-50 immunodecorated ribosomes and membranous structures (e.g. vesicles, endoplasmic reticulum), and many boutons which contained Alz-50-positive synaptic vesicles. None of the antisera against other Alzheimer-related proteins, including paired helical filament protein, ubiquitin, beta-amyloid protein, or heat-shock proteins specifically stained the population of cells labelled by Alz-50. Other tau antisera also did not specifically stain these cells. We conclude that Alz-50 recognizes an amino terminal epitope that is exposed on tau proteins within a single, discrete population of neurons in the normal sheep striatum. The presence of this epitope in a normal cell population raises the possibility that the early stages of AD degeneration may involve the activation of a normal cellular pathway that

Topics: Alzheimer Disease; Animals; Antigens; Blotting, Western; Corpus Striatum; Fluorescent Antibody Technique; Heat-Shock Proteins; Immunohistochemistry; Microscopy, Immunoelectron; NADPH Dehydrogenase; Neuropeptide Y; Parvalbumins; Sheep; Somatostatin

Somatostatin-like immunoreactivity (SLI) and neuropeptide Y-like immunoreactivity (NPYLI) were measured in the cerebral cortex of 49 patients with Alzheimer's disease (AD), and 9 elderly controls. Concentrations of SLI were lower in AD patients relative to controls in 9 of 10 cortical regions. In contrast, no significant differences in NPYLI concentrations between the two groups were observed in any of 10 regions. These studies suggest a dissociation between SLI deficits and NPYLI concentrations in the postmortem cerebral cortex of AD patients. The apparent sparing of NPYLI-containing neurons suggests that neuropeptide Y may be located within a separate group of neurons compared to somatostatin.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cadaver; Cerebral Cortex; Humans; Immune Sera; Infant, Newborn; Neuropeptide Y; Osmolar Concentration; Radioimmunoassay; Reference Values; Somatostatin; Tissue Distribution

Cholinergic neurons were studied by immunohistochemistry, with an antiserum against choline acetyltransferase (ChAT), in the basal forebrain (Ch1 to Ch4) of four patients with Alzheimer's disease (AD) and four control subjects. ChAT-positive cell bodies were mapped and counted in Ch1 (medial septal nucleus), Ch2 (vertical nucleus of the diagonal band), Ch3 (horizontal nucleus of the diagonal band) and Ch4 (nucleus basalis of Meynert). Compared to controls, the number of cholinergic neurons in AD patients was reduced by 50% on average. The interindividual variations in cholinergic cell loss were high, neuronal loss ranging from moderate (27%) to severe (63%). Despite the small number of brains studied, a significant correlation was found between the cholinergic cell loss and the degree of intellectual impairment. To determine the selectivity of cholinergic neuronal loss in the basal forebrain of AD patients, NPY-immunoreactive neurons were also investigated. The number of NPY-positive cell bodies was the same in controls and AD patients. The results (1) confirm cholinergic neuron degeneration in the basal forebrain in AD and the relative sparing of these neurons in some patients, (2) indicate that degeneration of cholinergic neurons in the basal forebrain contributes to intellectual decline, and (3) show that, in AD, such cholinergic cell loss is selective, since NPY-positive neurons are preserved in the basal forebrain.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Choline O-Acetyltransferase; Female; Humans; Male; Neurons; Neuropeptide Y; Parasympathetic Nervous System; Prosencephalon; Reference Values; Tissue Distribution

Neuropeptide Y, one of the most abundant polypeptides within the nervous system, is co-stored with catecholamines, especially norepinephrine (NE), thus suggesting its possible involvement in pathologies characterized by a noradrenergic impairment. In Parkinson's disease (PD), as well as in multiple system atrophy (MSA), a central noradrenergic deficit has been demonstrated, and in the dementia of Alzheimer type (DAT) an impaired noradrenergic transmission has been postulated. In this study we determined CSF NE and MHPG levels in 29 PD, 15 MSA, 22 DAT patients and in 36 controls, while CSF NPY-immunoreactivity (NPY-ir) levels were measured in 10 PD, 7 MSA, 10 DAT patients and 20 controls. PD, MSA, and DAT patients showed a significant reduction in CSF NPY-ir and NE levels compared with controls, while CSF MHPG levels resulted in a reduction in only the MSA group. Furthermore, an inverse correlation between either NE or MHPG levels and the duration of the orthostatic hypotension was found in MSA patients while for DAT patients the MHPG levels were directly correlated to the severity of cognitive impairment, and inversely to the duration of illness.

Topics: Adult; Aged; Alzheimer Disease; Female; Humans; Male; Methoxyhydroxyphenylglycol; Middle Aged; Neuropeptide Y; Norepinephrine; Parkinson Disease; Peripheral Nervous System Diseases; Severity of Illness Index; Shy-Drager Syndrome; Spinal Cord Diseases

Cholinergic neurons of the ventral pallidum and the dorsal pallidum (globus pallidus) were immunohistochemically investigated in patients suffering from Alzheimer disease (AD). Measurement of cholinergic neurons, stained with an antiserum against choline acetyltransferase (ChAT), revealed that their number was significantly reduced in both the dorsal pallidum (37.5%) and the ventral pallidum (65%) of AD patients (n = 4) when compared to control subjects (n = 3). No shrinkage of these cells was observed. The number of immunostained neuropeptide Y-containing neurons in the same structures was not different in controls and AD patients, indicating that the loss of cholinergic neurons was selective. These results combined with previous reports give further information upon which specific subsets of cholinergic neurons degenerate in AD.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cell Survival; Choline O-Acetyltransferase; Globus Pallidus; Humans; Immunohistochemistry; Neurons; Neuropeptide Y; Parasympathetic Nervous System; Reference Values; Staining and Labeling

Cerebrospinal fluid (CSF) measures of dynorphin A were compared in three groups. Alzheimer patients (n = 9), elderly depressives (n = 9), and age-matched normal controls (n = 9). The Alzheimer patients revealed a 40% decrease in CSF dynorphin compared with controls (36 +/- 15 versus 60 +/- 21 pg/ml, p less than 0.05). In contrast, other peptide measures [Neuropeptide Y (NPY), vasoactive intestinal peptide (VIP), and galanin] remained unchanged across groups. This finding was further supported when an additional 20 Alzheimer patients with similar clinical backgrounds also showed reduced CSF dynorphin (37 +/- 13 pg/ml). CSF dynorphin did not correlate significantly with clinical variables or other CSF measures of monoamine metabolites [i.e., 3-methoxy-4-hydroxyphenylglycol (MHPG), 5-hydroxyindoleacetic acid (5-HIAA), and homovanillic acid (HVA)]. Given the previous report of increased kappa binding of Alzheimer brains at autopsy, the authors speculate about a possible up-regulation of opiate receptors in Alzheimer's disease and suggest ways to test this hypothesis in vivo.

Topics: Aged; Alzheimer Disease; Brain; Depressive Disorder; Dynorphins; Female; Galanin; Homovanillic Acid; Humans; Hydroxyindoleacetic Acid; Male; Mental Recall; Methoxyhydroxyphenylglycol; Middle Aged; Neuropeptide Y; Neuropsychological Tests; Peptide Fragments; Peptides; Receptors, Opioid; Vasoactive Intestinal Peptide

For diagnostic purposes, a differentiation can be made between the locus coeruleus (LC) in normal brain and the LC, in senile dementia of the Alzheimer's type (SDAT) and Parkinson's disease (PD). The differentiation is based on findings concerning the morphological alterations of the TH-immunoreactive; neurons, on the topographical distribution of neuron loss within the length of the LC, and on the total reduction in cell number.

Topics: Adult; Aged; Aged, 80 and over; Alzheimer Disease; Biomarkers; Cell Count; Dopamine beta-Hydroxylase; Female; Galanin; Humans; Immunoenzyme Techniques; Locus Coeruleus; Male; Middle Aged; Nerve Tissue Proteins; Neurons; Neuropeptide Y; Parkinson Disease; Peptides; Tyrosine 3-Monooxygenase

A reduction in immune function has been found in patients with a major depressive disorder and in persons undergoing severe life stress. This study investigated the association between increased sympathetic nervous system activity and reduced natural killer (NK) cytotoxicity in depression and Alzheimer caregiver stress. NK activity and plasma concentrations of epinephrine, norepinephrine, and neuropeptide Y were measured in depressed patients (n = 19) and age- and gender-matched controls (n = 19), and in Alzheimer spousal caregivers (n = 48) and matched noncaregiver controls (n = 17). Plasma levels of neuropeptide Y, but not circulating basal levels of catecholamines, were significantly (P less than 0.01) elevated in the depressed patients and in the caregivers compared with respective controls. NK activity was significantly (P less than 0.001) lower in the depressed patients than in their controls, but not different between the caregivers and the noncaregiver controls. Circulating concentrations of neuropeptide Y, but not catecholamines, were inversely correlated (r = -0.31, P less than 0.001) with NK activity. In addition, multiple regression analyses demonstrated that the significant (P less than 0.01) association between neuropeptide Y and natural cytotoxicity was independent of the relative contribution of age and basal and dynamic levels of epinephrine and norepinephrine. These findings suggest that increased sympathetic nervous system activity and the release of neuropeptide Y may be associated with the modulation of NK cytotoxicity.

Topics: Alzheimer Disease; Caregivers; Case-Control Studies; Cytotoxicity, Immunologic; Depression; Epinephrine; Evaluation Studies as Topic; Female; Humans; Killer Cells, Natural; Male; Neuropeptide Y; Norepinephrine; Stress, Physiological; Sympathetic Nervous System

A direct synapse between catecholamine fibers and neuropeptide Y-containing neurons is demonstrated in rat cerebral cortex using an immunohistochemical double-staining method under the electron microscope. A new method to produce a selective reduction in cholinergic neurons in the basal forebrain without damage to the non-cholinergic neurons, passing fibers or other cholinergic systems, is described. This animal model seems to be very useful to analyze the pathogenesis of Alzheimer's disease and to examine the function of cholinergic neurons of the basal forebrain.

Topics: Acetylcholine; Alzheimer Disease; Animals; Catecholamines; Cerebral Cortex; Disease Models, Animal; Neurons; Neuropeptide Y; Rats

Immunocytochemical studies utilizing radioimmunoassay and morphological techniques have provided conflicting evidence for the involvement of somatostatin and neuropeptide Y in Alzheimer's disease (AD). However, previous investigators have not considered the effects of cortical atrophy in AD tissue on their findings. This study reports the numbers of somatostatin-like (SLI) and neuropeptide Y-like immunoreactive (NPYLI) neuronal perikarya and the length of SLI and NPYLI immunoreactive fibres, with appropriate corrections for atrophy in 6 control and 6 AD cases. There were significantly fewer SLI neurones in AD in layers II + III combined from the temporal cortex, and fewer NPYLI neurones in layers V + VI in both frontal and temporal cortices. Using a randomized method to quantify immunostained fibre length in the neuropil, an analysis of variance revealed no significant differences in the mean SLI or NPYLI fibre length per cortical strip between control and AD groups in frontal or temporal cortex. However, using a second measure of fibre length by tracing the fibres attached to consecutive immunostained perikarya, there were significant reductions in the AD brains in the mean fibre length per cell in layers V + VI for SLI in the temporal cortex, and for NPYLI in the frontal cortex. This reduction in fibre length per individual cell was presumably masked by the large variation in the fibre length found between cases using the randomized approach. It was concluded that in order to evaluate the involvement of these neuropeptides in AD from any measurements of concentration, it is essential to include some compensation for the extent of cortical atrophy that occurs with the disease.

Topics: Aged; Alzheimer Disease; Brain; Female; Humans; Immunohistochemistry; Male; Middle Aged; Neuropeptide Y; Somatostatin

The CSF levels of somatostatin-LI (SLI), neuropeptide Y (NPY-LI) and Delta Sleep Inducing Peptide (DSIP-LI) have been measured in patients with dementia of Alzheimer type (DAT) and dementia with frontotemporal degeneration of non-Alzheimer type (FTD). The distribution pattern of cortical degeneration differs between these two types of dementia. DAT shows degeneration of mainly temporo-parietal and temporo-limbic structures, whereas FTD discloses its main degeneration in the frontotemporal regions (Brun, 1987). The somatostatin-LI was significantly reduced both in DAT and FTD. NPY-LI showed a significant reduction in DAT but not in FTD. A tendency to a reduction with duration of the disease was observed in DAT whereas the contrary was noted in FTD. The DSIP-LI levels were reduced in DAT and slightly increased in FTD. The study provides an evidence of neurochemical differences between the two primary degenerative dementias.

Topics: Adult; Aged; Alzheimer Disease; Delta Sleep-Inducing Peptide; Dementia; Female; Frontal Lobe; Humans; Male; Middle Aged; Neuropeptide Y; Neuropeptides; Somatostatin; Temporal Lobe

Topics: Alzheimer Disease; Animals; Brain; Central Nervous System Diseases; Gene Expression Regulation; Neuropeptide Y; Receptors, Neuropeptide Y; Receptors, Neurotransmitter; Vasoconstrictor Agents

Neuropeptide Y (NPY) and peptide YY (PYY) receptor sites were studied in human brain using saturation binding experiments and receptor autoradiography. Additionally, the affinities and densities of [3H]NPY binding sites were compared in the temporal cortex, hippocampus and putamen of patients dying from Alzheimer's disease (AD) and aged matched controls. High densities of [3H]NPY binding sites were found in the putamen (192 +/- 32 fmol/mg protein), followed by the hippocampus (165 +/- 42 fmol/mg protein) and temporal cortex (118 +/- 19 fmol/mg protein). Receptor autoradiography revealed that these sites were especially concentrated in certain layers of the hippocampus, laminae I and IV-V of the temporal cortex and the amygdalo-hippocampal area. No significant changes in [3H]NPY binding affinities were seen between the AD and aged-matched groups (Kd ranges: 2.5-6.8 nM). However, significant decreases in [3H]NPY receptor densities (Bmax) were found in temporal cortex (-43%) and hippocampus (-49%) in AD brains. No significant change in [3H]NPY Bmax values was found in the putamen. It is therefore possible that decreases in [3H]NPY receptor densities may be associated to the degenerative process taking place in certain brain regions in AD, although further work will be necessary to confirm this hypothesis. Part of this work was presented at the 17th Annual Meeting of the Society for Neuroscience.

Topics: Aged; Alzheimer Disease; Autoradiography; Brain; Cell Membrane; Female; Hippocampus; Humans; Iodine Radioisotopes; Male; Middle Aged; Neuropeptide Y; Putamen; Receptors, Neuropeptide Y; Receptors, Neurotransmitter; Reference Values; Temporal Lobe

The cerebrospinal fluid neuropeptide Y level was measured by radioimmunoassay in 20 patients with probable Alzheimer's disease and in 19 controls. The mean level was lower in patients (69.5 +/- 36.7 pg/ml) than in controls (103 +/- 21.8 pg/ml; p less than 0.001). Patients with a disease duration of greater than 2 years had cerebrospinal fluid neuropeptide Y levels lower than those with shorter disease duration (p less than 0.02). These results suggest that neuropeptide Y containing cells may be involved in Alzheimer's disease. No correlation was found between neuropeptide Y levels and degree of cognitive impairment or age at disease onset.

Topics: Aged; Alzheimer Disease; Antibody Specificity; Female; Humans; Iodine Radioisotopes; Male; Middle Aged; Neuropeptide Y; Psychiatric Status Rating Scales; Radioimmunoassay

We tested whether the vulnerability of somatostatin (SST) neurons in senile dementia of the Alzheimer type (SDAT) depended upon their co-localization with neuropeptide Y (NPY). Density estimates of SST28- and NPY-immunoreactive neurons and percentage of double-labeled SST-NPY neurons were obtained in the cortex (areas 9 and 25) and the bed nucleus of stria terminalis (BST), in 6 SDAT and 5 control cases. Counts of senile plaques (SP) and neurofibrillary tangles (NFT) were done on thioflavin S stains. In both cortical areas, a decrease in the density of SST28-IR neurons was found in SDAT cases (-60% in area 25 and -80% in area 9), whereas density of NPY-IR neurons was unchanged. Accordingly, the proportion of single-labeled SST neurons decreased; this decrease was significantly correlated with SP (r = -0.89, P less than 0.001). We conclude that single SST-IR neurons, in cortical layers II-III, and V, are preferentially lost relative to co-localized SST-NPY neurons. In the BST, no significant reduction of SST-IR, NPY-IR neurons nor of the percentage of single labeled SST neurons was found, despite the presence of SP. Thus one subpopulation of SST neurons, defined by associated neurochemical characters (not co-localized with NPY nor with NADPH diaphorase) and by topography (cortical layers III and V) appears to be particularly vulnerable in SDAT. The potential importance of their position in neural circuitry is emphasized.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amygdala; Brain; Cerebral Cortex; Female; Humans; Male; Middle Aged; Neurofibrils; Neuropeptide Y; Somatostatin; Somatostatin-28

Cholinergic neurons were studied by immunohistochemistry with an antiserum against human choline acetyltransferase in the caudate nucleus, putamen, and ventral striatum (including the nucleus accumbens) of three patients with Alzheimer disease and three control subjects. Immunoreactive cell bodies were mapped and counted. In the ventral striatum of patients with Alzheimer disease, a 60% decrease in the number of cholinergic neurons was observed, whereas in the caudate nucleus and putamen values for control subjects and patients were similar. To determine whether all neurons in the ventral striatum were affected, neuropeptide Y-containing neurons were also immunostained, mapped, and counted. The number of these neurons was the same in control subjects and patients with Alzheimer disease, indicating that neuronal loss is not generalized in the ventral striatum and may be specific to the cholinergic population.

Topics: Acetylcholinesterase; Aged; Aged, 80 and over; Alzheimer Disease; Choline O-Acetyltransferase; Corpus Striatum; Humans; Immunoenzyme Techniques; Neurons; Neuropeptide Y; Reference Values

Topics: Alzheimer Disease; Brain; Brain Mapping; Corticotropin-Releasing Hormone; Humans; Neuropeptide Y; Parkinson Disease; Radioimmunoassay; Receptors, Nicotinic

Cerebrospinal fluid somatostatin and neuropeptide Y concentrations were measured in 26 healthy normal subjects, 27 patients with dementia of the Alzheimer type (DAT), and seven patients with DAT with extrapyramidal signs (EDAT). In healthy normal subjects, there was no significant correlation between age and either somatostatin or neuropeptide Y concentration. However, the concentrations of both peptides correlated significantly with each other. In patients with DAT and EDAT, the concentrations of somatostatin (17.5 +/- 5.0 and 16.4 +/- 5.0 pg/mL, respectively) were significantly reduced relative to age-matched control subjects (23.1 +/- 8.2 pg/mL) but were unrelated to dementia severity and did not change significantly during the progression of the disease. Neuropeptide Y concentrations did not differ significantly between the age-matched control, DAT, and EDAT groups (38.2 +/- 12.8, 37.0 +/- 12.3, and 30.3 +/- 7.8 pg/mL, respectively). These results suggest that in DAT, dysfunction of cortical somatostatin but not neuropeptide Y transmitter systems is reflected by reduced cerebrospinal fluid concentrations.

Topics: Adult; Aged; Aged, 80 and over; Aging; Alzheimer Disease; Dementia; Extrapyramidal Tracts; Female; Humans; Male; Middle Aged; Neuropeptide Y; Somatostatin

Somatostatin and neuropeptide Y are two neuropeptides that are of particular interest in Alzheimer's disease because they are reported to be depleted in cerebral cortex. In the present study we examined somatostatin, neuropeptide Y, and nicotinamide adenine dinucleotide phosphate (NADPH) diaphorase neurons in nine cortical regions in both normal and Alzheimer's disease brains. These three neurochemical markers show a high degree of co-localization (greater than 90%) in nonpyramidal neurons that are primarily distributed in cortical layers II-III, V-VI, and, most prominently, in infracortical white matter. The highest cell density was in temporal and parietal association cortex. The major morphological abnormality in Alzheimer's disease brains was a marked pruning and distortion of fiber plexuses with an apparent reduction in fiber density. In contrast, perikaryal density was preserved except for a reduction in parietal association cortex. Approximately 10 to 15% of senile plaques in the inferior temporal gyrus contained abnormal neurites. Additional abnormal collections of neurites without plaque cores were frequently found in layers II-III and V-VI. Neuropeptide Y and somatostatin were co-localized in abnormal neurites, suggesting an origin from local intrinsic neurons in which the two peptides are co-localized. Double immunofluorescence staining for both tau protein, a major antigenic component of paired helical filaments, and either somatostatin or neuropeptide Y showed that these neurons do not contain tau-immunoreactive neurofibrillary tangles. The morphological correlate of reduced somatostatin and neuropeptide Y content in Alzheimer's disease brain therefore appears to be a distortion and reduction in fiber plexuses. In addition, it is apparent that these neurons can develop widespread morphological abnormalities in the absence of neurofibrillary tangle formation.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Brain Chemistry; Cerebral Cortex; Fluorescent Antibody Technique; Humans; Immunoenzyme Techniques; Middle Aged; NADH, NADPH Oxidoreductases; NADPH Dehydrogenase; Neurons; Neuropeptide Y; Somatostatin

This study examined the amygdaloid complex in Alzheimer's disease (AD). We compared the distribution and morphology of somatostatin (SOM-) and neuropeptide Y-immunoreactive (NPY-IR) neurons in the amygdala with the distribution of neuritic plaques (NP) and acetylcholinesterase (AChE) staining patterns in various subnuclei. We found that in AD, there was an increase in the number of small, atrophic neurons for both SOM and NPY, and subregional analysis revealed similar size reductions in all subnuclei. In contrast, the highest density of NP was found in the corticomedial nuclei and densest staining for AChE in the basal nucleus. Although NPY- and SOM-IR fibers were occasionally associated with NP, a dense, morphologically preserved peptidergic fiber-network was found in all areas including subnuclei with high numbers of NP. Our study indicates that atrophic SOM- and NPY-IR neurons are not correlated with the subregional distribution of NP or cholinesterase staining pattern of the amygdala, and suggests that alterations in SOM and NPY neurons are not characteristics of the primary pathogenic process that underlie the formation of NP or cholinergic cell loss in AD.

Topics: Acetylcholinesterase; Aged; Aged, 80 and over; Alzheimer Disease; Amygdala; Cell Count; Humans; Immunohistochemistry; Middle Aged; Neurofibrils; Neurons; Neuropeptide Y; Somatostatin

Somatostatin-like immunoreactivity (SLI) and neuropeptide Y-like immunoreactivity (NPYLI) were measured in postmortem brain tissue from 12 control patients and 13 demented Parkinsonian patients who had Alzheimer-type cortical pathology. Twenty-two cortical regions were examined. Significant reductions in cortical SLI were found in 17 regions, while significant reductions in cortical NPYLI were found in nine regions. The reductions in SLI were typically 50-60%, while NPYLI reductions were 20-30%. These findings are similar to those in Alzheimer's disease (AD) and are consistent with a previous report of a dissociation between reductions in SLI and NPYLI in Parkinson's disease (PD) with dementia.

Topics: Aged; Alzheimer Disease; Female; Humans; Male; Middle Aged; Neuropeptide Y; Parkinson Disease; Somatostatin

The distribution of somatostatinlike immunoreactivity was studied in the hippocampal formation, retrohippocampal region, and temporal cortex in the human brain. Tissues from surgical biopsy and postmortem cases were used, and the immunogold/silver method on vibratome sections was introduced for routine applications in conjunction with primary antisera that recognise somatostatin-14 or somatostatin-28. Somatostatin-28 antisera readily stained numerous neurons, dendrites, and extensive axonal networks throughout the hippocampus and neighbouring cortex. Liquid phase absorption provided controls for specificity. The most prominent accumulations of somatostatin immunoreactive neurons and axons occurred in the hilus of the area dentata, in CA1, and in the entorhinal and perirhinal cortices. Axonal plexuses occurred throughout the hippocampal subfields but were particularly dense in those regions rich in somatostatin neurons. The distribution of somatostatin immunoreactive neurons and fibers parallels the distribution of neuropeptide Y (NPY) neurons and fibers in the hippocampus and cerebral cortex to a remarkable extent. Double labelling experiments with antisera against neuropeptide Y and somatostatin indicate a considerable frequency of coexistence of the two peptides in single neurons, particularly in large multipolar cortical neurons and also in the small bipolar white matter neurons. Regional variations exist in the amounts of coexistence found in the hippocampal subfields; somatostatin-NPY coexistence is particularly high in the hilus of the area dentata, the subicular complex, and the deep layers of the entorhinal and perirhinal cortices. In the hippocampi and temporal cortices in cases of Alzheimer-type dementia compared to those of age-matched control brains, there is a significant to severe loss of somatostatin immunoreactive neurons and axons. This loss is most severe in those regions with the highest indices of neurofibrillary tangles and neuritic plaques-the hilus of the area dentata, CA1, and the entorhinal and perirhinal cortices. Surviving somatostatin neurons are distorted with short dendrites and truncated axons. Neuritic plaques identified on double label experiments with thioflavin include somatostatin axons but not neurons.

Topics: Adolescent; Adult; Alzheimer Disease; Cerebral Cortex; Child; Child, Preschool; Female; Hippocampus; Histological Techniques; Humans; Male; Middle Aged; Neurons; Neuropeptide Y; Silver; Somatostatin

Somatostatin-like immunoreactivity (SLI) and neuropeptide Y-like immunoreactivity (NPYLI) were measured in subdissections of both normal and Alzheimer's disease (AD) striatum at 5 coronal levels. Concentrations of both neuropeptides were relatively homogeneously distributed in the coronal and anterior-posterior planes except for a trend towards increased concentrations in the tail of the caudate and the posterior putamen. The nucleus accumbens showed 2-3-fold higher concentrations of both SLI and NPYLI than the rest of the striatum. There were no significant differences between control and AD brains. The high concentrations of SLI and NPYLI in the nucleus accumbens suggest that this region may receive somatostatin-neuropeptide Y afferents and that somatostatin and neuropeptide Y may play a role in the modulation of motor activity.

Topics: Adult; Aged; Aged, 80 and over; Alzheimer Disease; Corpus Striatum; Female; Humans; Male; Middle Aged; Neuropeptide Y; Nucleus Accumbens; Somatostatin; Tissue Extracts

NPY-containing neuronal structures in the cerebral cortex of surgical tissue samples were compared to those in postmortem material by immunocytochemical methods. However, the quality of preservation of individual neurons and axonal and dendritic plexuses in the neuropil is unusually fine in the surgical specimens. This result is most likely attributable to the excellent fixation that can be regularly achieved by rapid and careful handling of tissue during and after surgical removal. The tissue is suitable for both light and electron microscopy, and the superior preservation also leads to intense, reliable antibody reactions. Postmortem tissue samples can provide good specimens for immunocytochemistry when properly handled as previously described. However the postmortem delays prior to fixation disrupt neuronal integrity in the immunostained structures. Nevertheless, postmortem material from carefully studied subjects of neurological diseases compared with age matched controls can provide valuable information.

Topics: Adolescent; Adult; Aged; Alzheimer Disease; Cerebral Cortex; Child; Child, Preschool; Female; Humans; Immune Sera; Immunoenzyme Techniques; Infant; Male; Microscopy, Electron; Middle Aged; Nerve Tissue Proteins; Neuropeptide Y; Postmortem Changes; Staining and Labeling; Tissue Preservation

We have observed dystrophic choline acetyltransferase (ChAT)-positive processes surrounding the amyloid core of neuritic plaques in human neocortex, amygdala and hippocampus, using a polyclonal anti-human ChAT antiserum. These data, and those from studies of the aged monkey by other investigators, provide a morphologic counterpart for the biochemical abnormality of the cholinergic system in Alzheimer's disease and senile dementia of the Alzheimer type.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amygdala; Brain; Cerebral Cortex; Choline O-Acetyltransferase; Hippocampus; Humans; Neuropeptide Y; Somatostatin; Substance P

Morphological changes in neocortical somatostatin- and neuropeptide-Y-immunoreactive cells in senile dementia of the Alzheimer type (SDAT) were studied using light-microscopic immunohistochemical methods. The density of somatostatin-immunoreactive cells in the neocortex did not decrease in cases of SDAT compared with aged normal subjects. However, many somatostatin-positive fibers were abnormally swollen and bulbous in shape and they were often observed within senile plaques. The morphology of these swollen and bulbous fibers was similar to that of the swollen neurites present in senile plaques demonstrated by the silver-impregnation method. Similar fiber abnormalities were observed in sections stained with antibodies to neuropeptide Y. Somatostatin-positive cells in aged normal subjects were distributed from layer II through to the subcortical white matter. These cells were multipolar, bitufted, or pyramidal in shape, with the majority of cells being of the multipolar type. Neuropeptide Y-positive cells also were distributed from layer II through to the subcortical white matter. Most of these cells were multipolar, but a few bipolar cells were also observed. We suggest that a primary degenerative process might begin at the fiber terminals of the somatostatin neuronal system in the neocortex in SDAT.

Topics: Aged; Alzheimer Disease; Cerebral Cortex; Humans; Immunoenzyme Techniques; Male; Nerve Tissue Proteins; Neuropeptide Y; Somatostatin

Topics: Alzheimer Disease; Brain; Brain Chemistry; Cerebral Cortex; Cholecystokinin; Choline O-Acetyltransferase; gamma-Aminobutyric Acid; Hippocampus; Humans; Nerve Tissue Proteins; Neurofibrils; Neuropeptide Y; Neurotransmitter Agents; Norepinephrine; Psychological Tests; Vasoactive Intestinal Peptide

The content of two neuropeptides, somatostatin (SRIF) and neuropeptide Y (NPY) has been determined in two cerebral cortical areas of Alzheimer's disease brain and in age-matched control brains. The content of SRIF-like immunoreactivity (SRIF-LI) was found to be decreased in Alzheimer temporal cortex (Brodmann area 21) compared to control temporal cortex. The decreased content of SRIF was significantly correlated with the observed number of neuritic plaques and neurofibrillary tangles. No difference was observed in NPY-LI between Alzheimer cerebral cortex and control cortex. Furthermore, no correlations were observed between NPY content and plaque count, neurofibrillary tangle estimate or SRIF content despite widespread reports of NPY/SRIF coexistence.

Topics: Aged; Alzheimer Disease; Cerebral Cortex; Frontal Lobe; Humans; Neurofibrils; Neuropeptide Y; Parietal Lobe; Somatostatin

Multiple neurotransmitter systems are affected in senile dementia of the Alzheimer's type (SDAT). Among them, acetylcholine has been most studied. It is now well accepted that the activity of the enzyme, choline acetyltransferase (ChAT) is much decreased in various brain regions including the frontal and temporal cortices, hippocampus and nucleus basalis of Meynert (nbm) in SDAT. Cortical M2-muscarinic and nicotinic cholinergic receptors are also decreased but only in a certain proportion (30-40%) of SDAT patients. For other systems, it appears that cortical serotonin (5-HT)-type 2 receptor binding sites are decreased in SDAT. This diminution in 5-HT2 receptors correlates well with the decreased levels of somatostatin-like immunoreactive materials found in the cortex of SDAT patients. Cortical somatostatin receptor binding sites are decreased in about one third of SDAT patients. Finally, neuropeptide Y and neuropeptide Y receptor binding sites are distributed in areas enriched in cholinergic cell bodies and nerve fiber terminals and it would be of interest to determine possible involvement of this peptide in SDAT. Thus, it appears that multi-drug clinical trials should be considered for the treatment of SDAT.

Topics: Alzheimer Disease; Binding Sites; Brain; Choline; Choline O-Acetyltransferase; Humans; Neuropeptide Y; Neurotransmitter Agents; Receptors, Muscarinic; Receptors, Neurotransmitter; Serotonin; Somatostatin

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cerebral Cortex; Humans; Male; Neuropeptide Y; Somatostatin

Choline acetyltransferase (ChAT) activity and neuropeptide Y (NPY) levels in post-mortem tissues from patients with histologically proven Alzheimer's disease were compared with age-matched neurologically normal control individuals. Despite the high NPY concentrations in human cerebral cortex, no significant abnormalities were found. However, ChAT activity was reduced throughout the cortex, without a relationship to areas of functional deficit, as previously identified using fluorodeoxyglucose. These results lend further support to the concept of Alzheimer's disease as a highly selective neurodegenerative disorder.

Topics: Alzheimer Disease; Cerebral Cortex; Choline O-Acetyltransferase; Humans; Nerve Tissue Proteins; Neuropeptide Y; Radioimmunoassay

Neuropeptide Y is a 36-amino acid peptide that is found in high concentrations in cerebral cortex and is contained in cortical neurons. We measured concentrations of this peptide in postmortem tissue from patients with Alzheimer's disease and controls using a sensitive and specific radioimmunoassay. High-performance liquid chromatography showed that more than 95% of immunoreactivity co-migrated with synthetic standards in both Alzheimer's disease and control frontal cortex. Significant reductions in neuropeptide Y-like immunoreactivity were found in eleven cortical regions, the hippocampus, and the locus ceruleus. The regions particularly affected included the temporal lobe, frontal lobe, and occipital cortex. As neuropeptide Y is co-localized with somatostatin in a considerable proportion of cortical neurons, the loss of immunoreactivity may in part reflect degeneration of these neurons. Further study of the selective vulnerability of these neurons in Alzheimer's disease cortex may provide clues to the nature of the underlying disease process.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cerebral Cortex; Chromatography, High Pressure Liquid; Female; Humans; Male; Neuropeptide Y; Radioimmunoassay

Although several studies have documented reduced concentrations of somatostatin-like immunoreactivity (SLI) in the cerebral cortex in Alzheimer's disease, there is controversy concerning the extent and importance of these changes. We measured SLI in brains obtained post mortem from 12 patients with pathologically confirmed Alzheimer's disease and from 13 neurologically normal controls. All major cortical and subcortical regions were examined. Widespread reductions of SLI in Alzheimer's disease cerebral cortex were found, with the most profound changes seen in temporal lobe; but there also were major reductions in both the frontal and occipital cortex. There were no significant reductions in subcortical regions. Characterization of SLI by high-pressure liquid chromatography showed no significant difference in profiles between Alzheimer's disease and control frontal cortex. These results suggest that the reduction in somatostatin immunoreactivity in Alzheimer's disease may be caused by degeneration of intrinsic somatostatin cortical neurons.

Topics: Acetylcholinesterase; Aged; Alzheimer Disease; Basal Ganglia; Cerebral Cortex; Chromatography, High Pressure Liquid; Female; Humans; Limbic System; Male; Middle Aged; Neuropeptide Y; Peptides; Radioimmunoassay; Temporal Lobe

Neurons identified by their immunoreactivity with antisera against neuropeptide Y (NPY) were studied in three selected areas of the cerebral cortex in brains from controls and in senile dementia of the Alzheimer type (ATD). Changes were more profound in temporal cortex than in parietal cortex, and more severe in parietal cortex than in frontal cortex, paralleling the severity of neuritic plaque formation and incidence of neurofibrillary tangles in these regions. NPY-i neurons became distorted, with enlarged misshapen cell somata and reduced, thickened, and gnarled dendrites. There was a sharp reduction in the extensiveness and delicacy of the axonal plexus; the reorganized axons were haphazard compared to the normal symmetry of these fibers. Besides the alteration in form and sizes, there were also appreciably fewer cells. Nevertheless, the NPY population is not eliminated. Double-label studies of NPY-i and thioflavin indicate that NPY-i fibers can participate in neuritic plaque formation although not all neuritic plaques contained NPY-i axons and not all NPY-i axons were associated with plaques. The surviving NPY cells were evident in all cortices examined, thus giving rise to the speculation that these peptide neurons may have unusual survival and reorganization potential even in terminal neurological disease.

Topics: Aged; Alzheimer Disease; Axons; Brain Chemistry; Cerebral Cortex; Female; Humans; Immune Sera; Immunoenzyme Techniques; Male; Nerve Degeneration; Nerve Tissue Proteins; Neurons; Neuropeptide Y; Postmortem Changes; Staining and Labeling

Alzheimer's disease, a form of senile dementia, is characterized by the presence of neuritic plaques and neurofibrillary tangles throughout the cortex and hippocampus. This study demonstrates the presence of neuropeptide Y-like immunoreactivity within 10-20% of neuritic plaques. Neuropeptide Y is a 36 amino acid peptide which is distributed unevenly throughout the brain and has an interneuronal location.

Topics: Alzheimer Disease; Cerebral Cortex; Fluorescent Dyes; Hippocampus; Humans; Nerve Tissue Proteins; Neurons; Neuropeptide Y; Tissue Distribution

Concentrations of neuropeptide Y (NPY) have been determined in 12 areas of control brains and compared to those found in brains from patients with Alzheimer's type dementia (ATD). The distribution of NPY in the control brains was compared with those reported previously. Highest concentrations were identified in the subcortical structures, in particular, nucleus accumbens (203 +/- 21.7 pmol/g), amygdala (136.7 +/- 15.8 pmol/g), and substantia innominata (109.0 +/- 12.6 pmol/g). A significant elevation in NPY concentrations was identified in the region of the substantia innominata of Alzheimer brains (controls: 109.0 +/- 12.6 pmol/g, ATD: 206 +/- 28.2 pmol/g, P less than 0.001). This change in NPY concentration was similar to the increase in somatostatin concentration in this region of ATD brain. In contrast, although cortical concentrations of somatostatin were reduced in ATD, no change was found in the concentrations of NPY in the 4 regions of cerebral cortex and the remaining subcortical areas examined.

Topics: Aged; Alzheimer Disease; Basal Ganglia; Cerebral Cortex; Choline O-Acetyltransferase; Corpus Striatum; Hippocampus; Humans; Hypothalamus; Nerve Tissue Proteins; Neuropeptide Y; Septum Pellucidum; Somatostatin; Substantia Innominata